US2023391864A1PendingUtilityA1
Vectorized anti-tnf-alpha antibodies for ocular indications

Assignee: REGENXBIO INCPriority: Oct 28, 2020Filed: Oct 28, 2021Published: Dec 7, 2023
Est. expiryOct 28, 2040(~14.3 yrs left)· nominal 20-yr term from priority
Inventors:Xu Wang Devin Mcdougald Joseph T. Bruder Ye Liu Olivier Danos Wei-Hua Lee Chunping Qiao Ewa Budzynski Mikayla Higgins Mi Shi
C07K 16/241C12N 15/86A61P 27/02C12N 2750/14143C12N 2750/14145A61K 39/12C12N 2710/10343C12N 2710/10041C12N 2710/10043A61K 2039/505A61K 2039/5256A61K 2039/54C07K 2317/24C07K 16/248
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References
Claims
Abstract

Compositions and methods are described for the delivery of a fully human post-translationally modified therapeutic monoclonal antibody, or an antigen binding fragment thereof, that binds to TNF-α, IL6 or IL6-R to a human subject for treatment of an ocular indication, particularly non-infectious uveitis. The nucleotide sequence encoding the antibody is delivered in a rAAV vector that targets ocular tissue cells for expression of the transgene.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A pharmaceutical composition for treating non-infectious uveitis in a human subject in need thereof, comprising an adeno-associated virus (AAV) vector having:
 (c) a viral capsid that has a tropism for ocular tissue cells; and   (d) an artificial genome comprising an expression cassette flanked by AAV inverted terminal repeats (ITRs), wherein the expression cassette comprises a transgene encoding a heavy chain and a light chain of a substantially full-length or full-length anti-TNFα mAb, anti-IL6 mAb, or anti-IL6R mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that promote expression of the transgene in human ocular tissue cells;   
       wherein said AAV vector is formulated for subretinal, intravitreal, intranasal, intracameral, suprachoroidal, or systemic administration to said human subject. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the viral capsid is at least 95% identical to the amino acid sequence of AAV serotype 1 (AAV1), serotype 2 (AAV2), serotype AAV2.7m8 (AAV2.7m8), serotype 3 (AAV3), serotype 3B (AAV3B), serotype 4 (AAV4), serotype 5 (AAV5), serotype 6 (AAV6), serotype 7 (AAV7), serotype 8 (AAV8), serotype rh8 (AAVrh8), serotype 9 (AAV9), serotype 9e (AAV9e), serotype rh10 (AAVrh10), serotype rh20 (AAVrh20), serotype rh39 (AAVrh39), serotype hu.37 (AAVhu.37), serotype rh73 (AAVrh73), or serotype rh74 (AAVrh74), serotype hu51 (AAV.hu51), serotype hu21 (AAV.hu21), serotype hu12 (AAV.hu12), or serotype hu26 (AAV.hu26). 
     
     
         3 . The pharmaceutical composition of  claim 1  or  2 , wherein the AAV capsid is AAV8, AAV3B, AAV2.7m8, or AAVrh73. 
     
     
         4 . The pharmaceutical composition of  claims 1  to  3 , wherein the ocular tissue cell is a cornea cell, an iris cell, a ciliary body cell, a schlemm&#39;s canal cell, a trabecular meshwork cell, a retinal cell, a RPE-choroid tissue cell, or an optic nerve cell. 
     
     
         5 . The pharmaceutical composition of  claims 1  to  4 , wherein the regulatory sequence includes a regulatory sequence from Table 1. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the regulatory sequence is a CAG promoter (SEQ ID NO: 74), a CB promoter (SEQ ID NO: 273 or 274), a human rhodopsin kinase (GRK1) promoter (SEQ ID NOS:77 or 217), a mouse cone arresting (CAR) promoter (SEQ ID NOS: 214-216), a human red opsin (RedO) promoter (SEQ ID NO: 212) or a Best1/GRK1 tandem promoter (SEQ ID NO: 275). 
     
     
         7 . The pharmaceutical composition of any of  claims 1  to  6 , wherein the transgene comprises a Furin/2A linker between the nucleotide sequences coding for the heavy and light chains of said mAb. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein said Furin 2A linker is a Furin/T2A linker having the amino acid sequence RKRR(GSG) APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NOS:143 or 144). 
     
     
         9 . The pharmaceutical composition of any of  claims 1  to  8 , wherein the transgene encodes a signal sequence at the N-terminus of the heavy chain and the light chain of said antigen-binding fragment that directs secretion and post translational modification in said human ocular tissue cells. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO:85) or a signal sequence from Table 2. 
     
     
         11 . The pharmaceutical composition of any of  claims 1  to  10 , wherein transgene has the structure:
 signal sequence-Heavy chain-Furin site-2A site-signal sequence-Light chain-PolyA. 
 
     
     
         12 . The pharmaceutical composition of any of  claims 1  to  11 , wherein the anti-TNFα antibody is adalimumab, infliximab, or golimumab, or an antigen binding fragment thereof. 
     
     
         13 . The pharmaceutical composition of any of  claims 1  to  12 , wherein the full-length mAb or the antigen-binding fragment comprises a heavy chain with an amino acid sequence of SEQ ID NO: 1 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 64 and a light chain with an amino acid sequence of SEQ ID NO: 2; a heavy chain with an amino acid sequence of SEQ ID NO: 3 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 65 and a light chain with an amino acid sequence of SEQ ID NO: 4; or a heavy chain with an amino acid sequence of SEQ ID NO: 5 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 65 and a light chain with an amino acid sequence of SEQ ID NO: 6. 
     
     
         14 . The pharmaceutical composition of any of  claims 1  to  13 , wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 26 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 27 encoding the light chain; a nucleotide sequence of SEQ ID NO: 28 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 29 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 30 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 31 encoding the light chain. 
     
     
         15 . The pharmaceutical composition of any of  claims 1  to  11 , wherein the antiIL6 or anti-IL6R antibody is satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilizumab, or tocilizumab, or an antigen binding fragment thereof. 
     
     
         16 . The pharmaceutical composition of any of  claim 1  to  11  or  15 , wherein the full-length mAb or the antigen-binding fragment comprises a heavy chain with an amino acid sequence of SEQ ID NO: 7 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 67 and a light chain with an amino acid sequence of SEQ ID NO: 8; a heavy chain with an amino acid sequence of SEQ ID NO: 9 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO:185 and a light chain with an amino acid sequence of SEQ ID NO: 10; a heavy chain with an amino acid sequence of SEQ ID NO: 11 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 68 and a light chain with an amino acid sequence of SEQ ID NO: 12; comprises a heavy chain with an amino acid sequence of SEQ ID NO: 13 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 69 and a light chain with an amino acid sequence of SEQ ID NO: 14; a heavy chain with an amino acid sequence of SEQ ID NO: 15 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 70 and a light chain with an amino acid sequence of SEQ ID NO: 16; a heavy chain with an amino acid sequence of SEQ ID NO: 17 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 71 and a light chain with an amino acid sequence of SEQ ID NO: 18; a heavy chain with an amino acid sequence of SEQ ID NO: 19 and a light chain with an amino acid sequence of SEQ ID NO: 20; or a heavy chain with an amino acid sequence of SEQ ID NO: 21 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 72 and a light chain with an amino acid sequence of SEQ ID NO: 22. 
     
     
         17 . The pharmaceutical composition of any of  claim 1 ,  11  or  15 - 16 , wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 32 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 33 encoding the light chain; a nucleotide sequence of SEQ ID NO: 34 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 35 encoding the light chain; a nucleotide sequence of SEQ ID NO: 36 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 37 encoding the light chain; wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 38 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 39 encoding the light chain; a nucleotide sequence of SEQ ID NO: 40 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 41 encoding the light chain; a nucleotide sequence of SEQ ID NO: 42 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 43 encoding the light chain; wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 44 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 45 encoding the light chain; or a nucleotide sequence of SEQ ID NO:183 encoding the heavy chain and a nucleotide sequence of SEQ ID NO:184 encoding the light chain. 
     
     
         18 . The pharmaceutical composition of  claims 1  to  17 , wherein the antigen-binding fragment is a Fab, a F(ab′) 2 , or an scFv. 
     
     
         19 . The pharmaceutical composition of any of  claims 1  to  18 , wherein the mAb or the antigen-binding fragment thereof is a hyperglycosylated mutant or wherein the Fc polypeptide of the mAb is glycosylated or aglycosylated. 
     
     
         20 . The pharmaceutical composition of any of  claims 1  to  19 , wherein the artificial genome is self complementary. 
     
     
         21 . The pharmaceutical composition of any of  claims 1  to  20  wherein the artificial genome is the construct EF1ac.Vh4i.Adalimumab.Fab scAAV, mU1a.Vh4i.Adalimumab.Fab scAAV, CAG.Adalimumab.IgG, CAG.Adalimumab.Fab, GRK1.Vh4i.Adalimumab.IgG, CB.VH4i.adalimumab.IgG, or Best1/GRK1.VH4i.adalimumab.IgG. 
     
     
         22 . A composition comprising an adeno-associated virus (AAV) vector having:
 a. a viral AAV capsid, that is optionally at least 95% identical to the amino acid sequence of AAV serotype 1 (AAV1), serotype 2 (AAV2), serotype 3 (AAV3), serotype 3B (AAV3B), serotype 4 (AAV4), serotype 5 (AAV5), serotype 6 (AAV6), serotype 7 (AAV7), serotype 8 (AAV8), serotype rh8 (AAVrh8), serotype 9 (AAV9), serotype 9e (AAV9e), serotype rh10 (AAVrh10), serotype rh20 (AAVrh20), serotype rh39 (AAVrh39), serotype hu.37 (AAVhu.37), serotype rh73 (AAVrh73), or serotype rh74 (AAVrh74), serotype hu51 (AAV.hu51), serotype hu21 (AAV.hu21), serotype hu12 (AAV.hu12), or serotype hu26 (AAV.hu26); and   b. an artificial genome comprising an expression cassette flanked by AAV inverted terminal repeats (ITRs), wherein the expression cassette comprises a transgene encoding a heavy and a light chain of a substantially full-length or full-length anti-TNFα mAb anti-IL6 antibody or anti-IL6R antibody, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that promote expression of the transgene in human ocular tissue cells;   c. wherein the transgene encodes a signal sequence at the N-terminus of the heavy chain and the light chain of said mAb that directs secretion and post translational modification of said mAb in ocular tissue cells.   
     
     
         23 . The composition of  claim 22 , wherein the ocular tissue cell is a cornea cell, an iris cell, a ciliary body cell, a schlemm&#39;s canal cell, a trabecular meshwork cell, a retinal cell, a RPE-choroid tissue cell, or an optic nerve cell. 
     
     
         24 . The composition of  claim 22  or  23 , wherein the AAV capsid is AAV2.7m8, AAV8, AAV3B, or AAVrh73. 
     
     
         25 . The composition of  claims 22  to  24 , wherein the anti-TNFα antibody is adalimumab, infliximab, or golimumab, or an antigen binding fragment thereof. 
     
     
         26 . The pharmaceutical composition of any of  claims 22  to  25 , wherein the full-length mAb or the antigen-binding fragment comprises a heavy chain with an amino acid sequence of SEQ ID NO: 1 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 64 and a light chain with an amino acid sequence of SEQ ID NO: 2; a heavy chain with an amino acid sequence of SEQ ID NO: 3 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 65 and a light chain with an amino acid sequence of SEQ ID NO: 4; or a heavy chain with an amino acid sequence of SEQ ID NO: 5 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 65 and a light chain with an amino acid sequence of SEQ ID NO: 6. 
     
     
         27 . The pharmaceutical composition of  claims 22  to  26 , wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 26 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 27 encoding the light chain; a nucleotide sequence of SEQ ID NO: 28 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 29 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 30 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 31 encoding the light chain. 
     
     
         28 . The pharmaceutical composition of any of  claims 22  to  27 , wherein the antiIL6 or anti-IL6R antibody is satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilizumab, or tocilizumab, or an antigen binding fragment thereof. 
     
     
         29 . The pharmaceutical composition of any of  claim 22  to  24  or  27 , wherein the full-length mAb or the antigen-binding fragment comprises a heavy chain with an amino acid sequence of SEQ ID NO: 7 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 67 and a light chain with an amino acid sequence of SEQ ID NO: 8; a heavy chain with an amino acid sequence of SEQ ID NO: 9 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO:185 and a light chain with an amino acid sequence of SEQ ID NO: 10; a heavy chain with an amino acid sequence of SEQ ID NO: 11 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 68 and a light chain with an amino acid sequence of SEQ ID NO: 12; comprises a heavy chain with an amino acid sequence of SEQ ID NO: 13 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 69 and a light chain with an amino acid sequence of SEQ ID NO: 14; a heavy chain with an amino acid sequence of SEQ ID NO: 15 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 70 and a light chain with an amino acid sequence of SEQ ID NO: 16; a heavy chain with an amino acid sequence of SEQ ID NO: 17 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 71 and a light chain with an amino acid sequence of SEQ ID NO: 18; a heavy chain with an amino acid sequence of SEQ ID NO: 19 and a light chain with an amino acid sequence of SEQ ID NO: 20; or a heavy chain with an amino acid sequence of SEQ ID NO: 21 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 72 and a light chain with an amino acid sequence of SEQ ID NO: 22. 
     
     
         30 . The pharmaceutical composition of any of  claim 22 - 24  or  28 - 29 , wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 32 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 33 encoding the light chain; a nucleotide sequence of SEQ ID NO: 34 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 35 encoding the light chain; a nucleotide sequence of SEQ ID NO: 36 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 37 encoding the light chain; wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 38 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 39 encoding the light chain; a nucleotide sequence of SEQ ID NO: 40 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 41 encoding the light chain; a nucleotide sequence of SEQ ID NO: 42 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 43 encoding the light chain; wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 44 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 45 encoding the light chain; or a nucleotide sequence of SEQ ID NO:183 encoding the heavy chain and a nucleotide sequence of SEQ ID NO:184 encoding the light chain. 
     
     
         31 . The composition of any of  claims 22  to  30 , wherein the transgene comprises a Furin/2A linker between the nucleotide sequences coding for the heavy and light chains of said mAb. 
     
     
         32 . The composition of any of  claims 22  to  31 , wherein the nucleic acid encoding a Furin 2A linker is incorporated into the expression cassette in between the nucleotide sequences encoding the heavy and light chain sequences, resulting in a construct with the structure: Signal sequence-Heavy chain-Furin site-2A site-Signal sequence-Light chain-PolyA. 
     
     
         33 . The composition of  claims 22  to  32 , wherein said Furin 2A linker is a Furin/T2A linker having the amino acid sequence RKRR(GSG) APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NOS:143 or 144). 
     
     
         34 . The composition of any of  claims 22  to  33 , wherein said signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO:85) or a signal sequence from Table 2. 
     
     
         35 . The composition of any of  claims 22  to  34 , wherein the artificial genome is self complementary. 
     
     
         36 . The composition of any of  claims 22  to  27  or  31  to  35 , wherein the artificial genome is the construct EF1ac.Vh4i.Adalimumab.Fab scAAV, mU1a.Vh4i.Adalimumab.Fab scAAV, CAG.Adalimumab.IgG, CAG.Adalimumab.Fab, GRK1.Vh4i.Adalimumab.IgG, CB.VH4i.adalimumab.IgG, or Best1/GRK1.VH4i.adalimumab.IgG. 
     
     
         37 . A method of treating non-infectious uveitis in a human subject in need thereof, comprising subretinally, intravitreally, intranasally, intracamerally, suprachoroidally, or systemically administering to the subject a therapeutically effective amount of a composition comprising a recombinant AAV comprising a transgene encoding an anti-TNFα mAb, anti-IL6 mAb, or anti-IL6R mAb, or antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in ocular tissue cells. 
     
     
         38 . A method of treating non-infectious uveitis in a human subject in need thereof, comprising: subretinally, intravitreally, intranasally, intracamerally, suprachoroidally, or systemically administering to said subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding an anti-TNFα mAb, anti-IL6 mAb, or anti-IL6R mAb, or antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human ocular tissue cells, so that a depot is formed that releases a human post-translationally modified (HuPTM) form of anti-TNFα mAb, anti-IL6 mAb, or anti-IL6R mAb or antigen-binding fragment thereof. 
     
     
         39 . The method of  claim 37  or  38  wherein the anti-TNFα mAb is adalimumab, infliximab or golimumab. 
     
     
         40 . The method of  claims 37  to  39 , wherein the full-length anti-TNFα mAb or the antigen-binding fragment comprises a heavy chain with an amino acid sequence of SEQ ID NO: 1 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 64 and a light chain with an amino acid sequence of SEQ ID NO: 2; or a heavy chain with an amino acid sequence of SEQ ID NO: 3 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 65 and a light chain with an amino acid sequence of SEQ ID NO: 4; a heavy chain with an amino acid sequence of SEQ ID NO: 5 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 65 and a light chain with an amino acid sequence of SEQ ID NO: 6. 
     
     
         41 . The method of  claims 37  to  40 , wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 26 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 27 encoding the light chain; a nucleotide sequence of SEQ ID NO: 28 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 29 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 30 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 31 encoding the light chain. 
     
     
         42 . The method of any of  claims 37  to  38 , wherein the antiIL6 or anti-IL6R antibody is satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilizumab, or tocilizumab, or an antigen binding fragment thereof. 
     
     
         43 . The method of any of  claim 37  to  38  or  42 , wherein the full-length mAb or the antigen-binding fragment comprises a heavy chain with an amino acid sequence of SEQ ID NO: 7 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 67 and a light chain with an amino acid sequence of SEQ ID NO: 8; a heavy chain with an amino acid sequence of SEQ ID NO: 9 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO:185 and a light chain with an amino acid sequence of SEQ ID NO: 10; a heavy chain with an amino acid sequence of SEQ ID NO: 11 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 68 and a light chain with an amino acid sequence of SEQ ID NO: 12; comprises a heavy chain with an amino acid sequence of SEQ ID NO: 13 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 69 and a light chain with an amino acid sequence of SEQ ID NO: 14; a heavy chain with an amino acid sequence of SEQ ID NO: 15 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 70 and a light chain with an amino acid sequence of SEQ ID NO: 16; a heavy chain with an amino acid sequence of SEQ ID NO: 17 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 71 and a light chain with an amino acid sequence of SEQ ID NO: 18; a heavy chain with an amino acid sequence of SEQ ID NO: 19 and a light chain with an amino acid sequence of SEQ ID NO: 20; or a heavy chain with an amino acid sequence of SEQ ID NO: 21 and optionally an Fc polypeptide with an amino acid sequence of SEQ ID NO: 72 and a light chain with an amino acid sequence of SEQ ID NO: 22. 
     
     
         44 . The method of any of  claims 37  to  38  or  42  to  43 , wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 32 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 33 encoding the light chain; a nucleotide sequence of SEQ ID NO: 34 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 35 encoding the light chain; a nucleotide sequence of SEQ ID NO: 36 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 37 encoding the light chain; wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 38 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 39 encoding the light chain; a nucleotide sequence of SEQ ID NO: 40 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 41 encoding the light chain; a nucleotide sequence of SEQ ID NO: 42 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 43 encoding the light chain; wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 44 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 45 encoding the light chain; or a nucleotide sequence of SEQ ID NO:183 encoding the heavy chain and a nucleotide sequence of SEQ ID NO:184 encoding the light chain. 
     
     
         45 . The method of  claims 37  to  44 , wherein the ocular tissue cell is a cornea cell, an iris cell, a ciliary body cell, a schlemm&#39;s canal cell, a trabecular meshwork cell, a retinal cell, a RPE-choroid tissue cell, or an optic nerve cell. 
     
     
         46 . The method of any of  claims 37  to  44  wherein the viral capsid is at least 95% identical to the amino acid sequence of an AAV serotype 1 (AAV1), serotype 2 (AAV2), serotype AAV2.7m8 (AAV2.7m8), serotype 3 (AAV3), serotype 3B (AAV3B), serotype 4 (AAV4), serotype 5 (AAV5), serotype 6 (AAV6), serotype 7 (AAV7), serotype 8 (AAV8), serotype rh8 (AAVrh8), serotype 9 (AAV9), serotype 9e (AAV9e), serotype rh10 (AAVrh10), serotype rh20 (AAVrh20), serotype rh39 (AAVrh39), serotype hu.37 (AAVhu.37), serotype rh73 (AAVrh73), or serotype rh74 (AAVrh74), serotype hu51 (AAV.hu51), serotype hu21 (AAV.hu21), serotype hu12 (AAV.hu12), or serotype hu26 (AAV.hu26). 
     
     
         47 . The method of any of  claims 37  to  46 , wherein the AAV capsid is AAV2.7m8, AAV8, AAV3B, or AAVrh73. 
     
     
         48 . The method of any of  claims 37  to  46 , wherein the regulatory sequence includes a regulatory sequence from Table 1 or Table 1a. 
     
     
         49 . The method of  claim 48 , wherein the regulator sequence is a CAG promoter (SEQ ID NO: 74), a CB promoter (SEQ ID NO: 273 or 274), human rhodopsin kinase (GRK1) promoter (SEQ ID NOS:77 or 217), a mouse cone arresting (CAR) promoter (SEQ ID NOS: 214-216), a human red opsin (RedO) promoter (SEQ ID NO: 212) or a Best1/GRK1 tandem promoter (SEQ ID NO: 275). 
     
     
         50 . The method of any of  claims 37  to  49 , wherein the transgene comprises a Furin/2A linker between the nucleotide sequences coding for the heavy and light chains of said mAb. 
     
     
         51 . The method of  claim 50 , wherein said Furin 2A linker is a Furin/T2A linker having the amino acid sequence RKRR(GSG) APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NOS:143 or 144). 
     
     
         52 . The method of any of  claims 37  to  51 , wherein the transgene encodes a signal sequence at the N-terminus of the heavy chain and the light chain of said antigen-binding fragment that directs secretion and post translational modification in said human ocular tissue cells. 
     
     
         53 . The method of  claim 52 , wherein said signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO:85) or a signal sequence from Table 2. 
     
     
         54 . The method of any of  claims 37  to  53 , wherein transgene has the structure: Signal sequence-Heavy chain-Furin site-2A site-Signal sequence-Light chain-PolyA. 
     
     
         55 . The method of any of  claims 37  to  54 , wherein the mAb is a hyperglycosylated mutant or wherein the Fc polypeptide of the mAb is glycosylated or aglycosylated. 
     
     
         56 . The method of any of  claims 37  to  55  wherein the mAb contains an alpha 2,6-sialylated glycan. 
     
     
         57 . The method of any of  claims 37  to  56  wherein the mAb is glycosylated but does not contain detectable NeuGc and/or α-Gal. 
     
     
         58 . The method of any of  claims 37  to  57  wherein the mAb contains a tyrosine sulfation. 
     
     
         59 . The method of any of  claims 37  to  58  in which production of said HuPTM form of said mAb or antigen-binding fragment thereof is confirmed by transducing human ocular tissue cells in culture with said recombinant nucleotide expression vector and expressing said mAb or antigen-binding fragment thereof. 
     
     
         60 . The method of  claim 37  or  59 , wherein the therapeutically effective amount is determined to be sufficient to maintain a concentration of at least 10 ng/ml in aqueous humor, vitreous humor, RPE, retina, and/or anterior segment/chamber. 
     
     
         61 . The method of  claim 37  or  60 , wherein the therapeutically effective amount is determined to be sufficient to improve best corrected visual acuity (BCVA) by &gt;=2 ETDRS lines or increase in logMAR, reduced inflammatory activity of the anterior and posterior chamber according to the SUN classification, and/or reduction in grade of vitreous haze. 
     
     
         62 . The method of any of  claims 37  to  61 , wherein the rAAV is self complementary. 
     
     
         63 . The method of any of  claims 37  to  62  wherein the transgene within the construct EF1ac.Vh4i.Adalimumab.Fab scAAV, mU1a.Vh4i.Adalimumab.Fab scAAV, CAG.Adalimumab.IgG, CAG.Adalimumab.Fab, GRK1.Vh4i.Adalimumab.IgG, CB.VH4i.adalimumab.IgG, or Best1/GRK1.VH4i.adalimumab.IgG. 
     
     
         64 . A method of producing recombinant AAVs comprising:
 (c) culturing a host cell containing:
 (i) an artificial genome comprising a cis expression cassette flanked by AAV ITRs, wherein the cis expression cassette comprises comprising a transgene encoding a substantially full-length or full-length anti-TNFα mAb, anti-IL6, or anti-IL6R or antigen-binding fragment thereof, operably linked to one or more regulatory sequences that promote expression of the transgene in human ocular tissue cells; 
 (ii) a trans expression cassette lacking AAV ITRs, wherein the trans expression cassette encodes an AAV rep and an AAV capsid protein operably linked to expression control elements that drive expression of the AAV rep and the AAV capsid protein in the host cell in culture and supply the AAV rep and the AAV capsid protein in trans, wherein the capsid has ocular tissue cell tropism; 
 (iii) sufficient adenovirus helper functions to permit replication and packaging of the artificial genome by the AAV capsid protein; and 
   (d) recovering recombinant AAV encapsidating the artificial genome from the cell culture.   
     
     
         65 . The method of  claim 64 , wherein the transgene encodes a substantially full-length or full-length mAb or antigen binding fragment that comprises the heavy and light chain variable domains of adalimumab, infliximab, golimumab, satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilizumab, or tocilizumab wherein the AAV capsid protein is an AAV2.7m8, AAV8, AAV3B, or AAVrh73, capsid protein. 
     
     
         66 . The method of  claim 64  or  65 , wherein the ocular tissue cell is a cornea cell, an iris cell, a ciliary body cell, a schlemm&#39;s canal cell, a trabecular meshwork cell, a retinal cell, a RPE-choroid tissue cell, or an optic nerve cell. 
     
     
         67 . A host cell containing:
 d. an artificial genome comprising a cis expression cassette flanked by AAV ITRs, wherein the cis expression cassette comprises comprising a transgene encoding a substantially full-length or full-length anti-TNFα mAb, anti-IL6 mAb or anti-IL6R mAb, or antigen-binding fragment thereof, operably linked to one or more regulatory sequences that promote expression of the transgene in human ocular tissue cells;   e. a trans expression cassette lacking AAV ITRs, wherein the trans expression cassette encodes an AAV rep and an AAV capsid protein operably linked to expression control elements that drive expression of the AAV rep and the AAV capsid protein in the host cell in culture and supply the AAV rep and the AAV capsid protein in trans, wherein the capsid has ocular tissue cell tropism;   f. sufficient adenovirus helper functions to permit replication and packaging of the artificial genome by the AAV capsid protein.   
     
     
         68 . The host cell of  claim 67 , wherein the transgene encodes a substantially full-length or full-length mAb or antigen binding fragment that comprises the heavy and light chain variable domains of adalimumab, infliximab, golimumab, satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilizumab, or tocilizumab. 
     
     
         69 . The host cell of  claim 67  or  68 , wherein the AAV capsid protein is an AAV2.7m8, AAV8, AAV3B, or AAVrh73 capsid protein. 
     
     
         70 . The host cell of  claims 67  to  69 , wherein the ocular tissue cell is a cornea cell, an iris cell, a ciliary body cell, a schlemm&#39;s canal cell, a trabecular meshwork cell, a retinal cell, a RPE-choroid tissue cell, or an optic nerve cell.
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